This would make an interesting Pokemon game if it did happen! The Pokemon community would be split: half of the community would be outraged by the drastic change of gym leaders, pokemon and characters. The other half would be thrilled by the change.
I think that Game Freak could pull it off successfully, but what would be the point? If they're going to change things entirely, then they might as well set the scene in an entirely new region. This will bring in more fans and will please new fans. I do think that GameFreak could pull it off. Things would be strange, but I think that they could make it worth and I think the game would attract many more fans. Who knows, it may attract more fans than if they created an entirely new region, who knows!
Gawd this was hard to choose from, but I guess this type of game would best fit in the Sinnoh region but I'd rather like it in the Kanto region. I know that there have been like a billion remakes of Red and Blue but I think that it would be the coolest to implement this type of gameplay back in the Kant region because that's where we all started out. Everything is older and more primitive in the Pokemon world. Replace everything with new, state of the art gyms and new, different looking Pokemon and that changes the Pokemon experience drastically. It would change the Pokemon catching and training experience drastically. Instead of versing a rock gym leader first, you would be versing Cilan or his brothers. They have a normal type and a fire/water/grass type Pokemon which you would have to train and account for. The hardest gym would probably be the dragon gym, or the 5th. or 6th. gym because of the typing and the geography which you will have to deal with. Also, if you played in the Kanto region you may have a chance to skip a gym then go back and verse it later which could either help or hurt you. Then there's the Elite four. You would probably have to train more for that too.
I think that the Sinnoh region would fit best for the Unova region because it is the most modern region besides the Unova region. It has many of the attractions that the Unova region provided. The gyms are probably the most similar between the regions as well. The only gym that the Sinnoh region doesn't feature is a dragon type (Volkner's gym is more random than anything lol). Anyways, each region has towns that are similar, trainers that are similar, and the differences in Pokemon would make as big of a change than if you shifted with Johto or Kanto.
If GameFreak implemented this I would think that the Unova region and the region they based the game in should team up.For example, if the game was set in Kanto then Team Rocket and Plasma would team up). You would have to defeat both parties to save the region. At the end when you would fight their bosses (Giovanni's son and robot Ghetsis), N and Red would come to help you! Throughout your quest, you would visit with the old gym leaders of the region for advice and for help. It would be essential to talk to them and some you may need to even battle. You would meet up with Giovanni at one point and he would change. You would talk about Mewtwo and new Pokemon and "treatments" that Team Rocket would discover. You would also find out how Team Rocket and Team Plasma joined forces. The gameplay would have seasons, also there would be new towns and features in towns to entertain. After you beat the game there would be a sage mode where youcould travel back in time and verse the gym leaders when they were young. Their Pokemon would be harder. You would then verse the older Elite Four and Red at the end. After that, you would return to the present and N would give you a present. This would set the tone fr a new Pokemon game leaving fans excited!
Also, Team Ghetsis and Team Rocket would form a transfusion of Mewtwo/Mew and Reshiram/Zekrom depending on what game you buy. You would have to defeat it and would have the option of catching it after you had beaten Sage Mode.